Prostaglandin E₂ (PGE₂) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE₂ generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE₂-deficient ptges^−/− mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE₂-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE₂ deficiency depend on thromboxane A₂ and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges^−/− mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)₁ and EP₂ receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE₂ deficiency. Thus, PGE₂ controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.